For solubilization of non-polar compounds, either organic solvents or detergents are routinely used. Water soluble compounds with molecules forming a cavity into which non-polar compounds can be included can be used instead of solvents and detergents; cyclodextrins are an example of such compounds.
Cyclodextrins are a group of cyclic oligosaccharides in which glucopyranosyl residues are joined by alpha (1 to 4) glycoside linkages. Three cyclodextrins are of particular interest: alpha-, beta- and gamma-. They have, respectively, six, seven or eight glucopyranosyl residues. Since each of the glucopyranosyl residues has two secondary hydroxyls (located at the principal, wide, entry to the cavity) and one primary hydroxyl (located on the narrow opening of the cavity), alpha-, beta- and gamma-cyclodextrins have, respectively, 18, 21 or 24 hydroxyls, any of which can be alkylated.
Previous art related to epichlorohydrin:
Reactions of cyclodextrins with epichlorohydrin have been repeatedly investigated. Wiedenhof et al. (Starke, Vol. 21, pp. 119-123 (1969)) summarized the initial results. Cyclodextrin and epichlorohydrin were condensed in concentrated aqueous solutions with a strong base (e.g., 10% sodium hydroxide) and, depending on conditions, water soluble or water insoluble products were obtained. These products were called by Wiedenhof, et al. and others water soluble polymers or E-resins to denote that their molecules contain multiple cyclodextrin residues joined together by residues derived from epichlorohydrin. Wiedenhof et al. identified correctly these and other epichlorohydrin derived residues attached to cyclodextrins; dihydroxypropyl ether groups were one of the epichlorohydrin residues Wiedenhof et al. identified.
The matter was re-investigated by Fenyvesi et al. (communicated as a lecture in October 1981 and published subsequently in Proceedings of the First International Symposium on Cyclodextrins, D. Reidel Publishing Company, Dordrecht, Holland, 1982, pp. 345-356). Fenyvesi et al. found that products previous investigators called water soluble polymers are not really polymers. Fenyvesi et al. described seven different preparations made from beta-cyclodextrin and epichlorohydrin. Their data show that these preparations contained compounds with just one cyclodextrin per molecule (i.e., were partial dihydroxypropyl ethers of cyclodextrins). Their preparations also contained compounds which had just a few cyclodextrin residues per molecule (in further discussion we refer to these as oligomers). Nevertheless, through power of precedent, Fenyvesi et al. continued to use the term "polymer" for their products and this name has remained in use to present.
Fenyvesi et al., furthermore, tested and found the products made from beta-cyclodextrin and epichlorhydrin form inclusion complexes (and solubilize) compounds which according to Remington's Pharmaceutical Sciences (.sub.15 th edition, Mack Publishing Company, Easton, Pa., 1975) have direct uses in pharmaceutics. Fenyvesi et al. described pharmaceutical formulations of indomethacin (analgesic and antipyretic agent), benzoic acid (antifungal agent), cholic acid (digestant) and anethole (flavoring agent). Fenyvesi et al. did not unequivocally specify which of their preparation were used in these experiments, but gave full characterization of all of their preparations, from which the minimal concentration of partial dihydroxypropyl ethers of beta-cyclodextrin in these preparations can be calculated. Fenyvesi et al. taught that the mixtures contained molecules of molecular weight ranging from 1200 to 10,000 daltons. The pharmaceutical formulations made by Fenyvesi et al. had the form of aqueous solutions and previous art establishes that further ingredients can be added to solutions of inclusion complexes, or these solutions can be freeze dried, without complications.
At a later time, European Patent 0 149 197 Bl was awarded to Brauns and Muller claiming pharmaceutical formulations which encompass the teachings of Fenyvesi containing inclusion complexes of medicinal substances with "partially etherified cyclodextrin, the ether substituent of which are ... or dihydroxypropyl groups." The partially etherified beta-cyclodextrin, the ether substituent of which are ". . . dihydroxypropyl groups" is just a chemically synonymous name to the "cyclodextrin-glycerol-ether" of Fenyvesi et al. European Patent 0 149 197 Bl does not teach the preparation or describe any particular use of the di-hydroxypropyl ethers of cyclodextrins and does not address the previous art of Fenyvesi, et al.
Some aspects of the present invention are to be considered novel extensions of previous art by Fenyvesi et al., both with respect to preparation and uses employing new conditions of controlled basicity at minimal effective level in the reaction mixture, the products containing mainly molecules with just one cyclodextrin unit can be made and these possess new structural elements. Nevertheless, analysis of prior art shows that pharmaceutical uses of compositions of matter of this invention are not covered by description or claims in European Patent 0 149 197 Bl. European Patent 0 149 197 Bl and the earlier art of Fenyvesi et al neither describe how to make or use the instant invention. (It should be noted that while the patent claim specifically encompasses dihydroxypropyl cyclodextrins of Fenyvesi.) Specifically, Fenyvesi described pharmaceutical formulations containing inclusions complexes of medicinals with cyclodextrin derivatives of which 87% or less were "cyclodextrin-glycerol-ethers" which had just one cyclodextrin residue per molecule or dihydroxypropyl ethers of cyclodextrins by another name. The concentrations of dihydroxypropyl ethers of cyclodextrins in the materials described in the present invention are lower than those in the materials of Fenyvesi et al. The inclusions complexes containing medicinals with the derivatives of cyclodextrins described herein are neither disclosed nor claimed in European patent 0 149 197 Bl.
Previous art related to vicinal dihalides:
No records of a reaction of cyclodextrins with 1,2-dichloroethane, 1,2-dichloropropane, or their congeners were found.
Previous art related to methylation:
This reaction was a subject of many investigations. Chemically individual methyl derivatives of cyclodextrins were prepared either by a several step synthesis or without control of basicity during the reaction. The preparation of randomly methylated cyclodextrin derivatives, well suited for solubilization of non-polar compounds, was described in a European patent publication 0 646 602 Al; this patent publication also analyzed related previous art. This publication claims methods of reacting cyclodextrins with alkylating agents by a method wherein the cyclodextrins are dissolved in a fraction of the total base used and, thereafter, the alkylating agent and the remaining base are added. The novel process disclosed and claimed herein differs from the present invention in that under previous methods the basicity of the reaction mixture was essentially uncontrolled. Consequently, the type of distribution between the secondary and primary hydroxyls is quite different from the distributions obtained by the method of the present invention. Methods described in European patent publication 0 646 602 Al produce up to 62% of methyl groups on secondary hydroxyls. Methods of other previous art analyzed in the same publication introduce up to 52% of methyls to secondary hydroxyls.
Previous art related to alkylation by other reagents with one alkylating group:
In the previously described reactions of this type, the basicity of the reaction was neither controlled nor kept at its minimal effective level. For example, in alkylation of beta-cyclodextrins with sultones described in U.S. Pat. No. 5,134,127, the concentration of sodium hydroxide in the reaction mixtures was recommended to be, "set at a level higher than 10% (wt/wt), preferably in the range of 40-60% (wt/wt)." Products of the alkylation performed at such high basicity contained some starting cyclodextrin, which had to be removed by purification. When basicity of the reaction mixture is kept constant and at minimal effective level, as described in this invention, products without contaminating starting cyclodextrins can be obtained.